The inflammatory processes have always received great attention in science for being the first biological sign in any abnormality state of a medical condition.
Inflammation is fundamentally a protection response triggered by physical, chemical and biological stimulus that may lead to disturbances that can culminate in tissue necrosis.
In the '70s, after Vane and colleagues (see Vane, J. R. (1971). “Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs”. Nature-New Biology 231(25):232-5) demonstrated the participation of prostaglandins as mediators of inflammation, through its inhibition by acetyl salicylic acid, the research have intensified with the development of uncountable families of anti inflammatory drugs, especially the ones known as non-steroidal anti inflammatory (NSAI) drugs (see ROBERTS, L. J.; MORROW, J. D. “Analgesic-antipyretic and antiinflamatory agents and drugs employed in the treatment of gout”. In: HARMAN, J. G.; LIMBIRD, L. E. (Eds.). Goodman & Gilman's: the pharmacological bases of therapeutics. New York: MacGraw-Hill, 2001, p. 687-732).
The NSAIs are drugs largely used, constituting an important medicamental resource in despite of the possibility of causing serious side effects, such as gastric irritations (high incidence) and hypertension, causing also liver, kidney, spleen, blood and bone marrow damages (see RANG, H. P.; DALE, M. M.; RITTER, J. M. Farmacologia. Fourth ed. Rio de Janeiro: Guanabara Koogan, 2001, p. 692).
The mechanism of action for NSAI drugs encompasses the inhibition of cyclooxygenases (COX), denominated COX-1 (constitutive form and its inducible form COX-2), interfering in the synthesis of prostaglandins (PG) and reducing the inflammatory reactions.
The prostaglandins perform important physiological functions; among them is gastrintestinal cytoprotection and vascular homeostasis.
COX-1 is responsible for the synthesis of cytoprotector prostaglandins of the gastrintestinal tract and for the synthesis of tromboxans that participate in the formation of platelets aggregation (see Allison, Howatson, Torrence, Lee and Russell. “Gastrointestinal Damage Associated with the Use of Nonsteroidal Antiinflammatory Drugs”. N. Engl. J. Med. (1992) Vol. 327, pp. 749-754). Regarding COX-2, it is known that it is characterized for presenting a short life, and its production occurs from stimulus in response to endotoxins and cytotoxins. It is important to highlight the fact that COX-2 inhibits the prostaglandins responsible for biosynthesis in inflammatory cells (monocytes and macrophages) as well as in the central nervous system (see Masferrer, Zweifel, Manning, Hauser, Leahy, Smith, Isakson and Seibert, “Selective Inhibition of Inducible Cyclooxygenase-2 in vivo is Antiinflammatory and Nonulcerogenic”, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol. 91, pp. 3228-3232; Vane, Mitchell, Appleton, Tomlinson, Bishop-Bailey, Croxtall and Willoughby, “Inducible Isoforms of Cyclooxygenase and Nitric Oxide Synthase in Inflammation”, Proc. Natl. Acad. Sci. U.S.A. (1994) Vol. 91, pp. 2046-2050; Harada, Hatanaka, Saito, Majima, Ogino, Kawamura, Ohno, Yang, Katori and Yamamoto, “Detection of Inducible Protaglandin H Synthase-2 in Cells in the Exudate of Rat Carrageenin-Induced Pleurisy”, Biomed. Res. (1994) Vol. 15, pp. 127-130; Katori, Harada, Hatanaka, Kawamura, Ohno, Aizawa and Yamamoto, “Induction of Prostaglandin H Synthase-2 in Rat Carrageenin-Induced Pleurisy and Effect of a Selective COX-2 Inhibition”, Advances in Prostaglandin, Thromboxana, and Leukotriene Research (1995) Vo. 23, pp. 345-347; and Kennedy, Chan, Culp and Cromlish, “Cloning and Expression of Rat Prostaglandin Endoperoxide Synthase (Cyclooxigenase-2) cDNA”, Biochem. Biophys. Res. Commun. (1994) Vol. 197, pp. 494-500).
The traditional NSAI drugs such as ASA (acetyl salicylic acid), diclophenac, ibuprophen, and naproxen inhibit COX-1 and COX-2. This non-selectivity of NSAI drugs leads also to the inhibition of prostaglandins, which are important for participating in gastric protection.
In order to reduce side effects caused by traditional NSAI drugs, an enormous quantity of COX-2 selective drugs (COX-2 inhibitors) have been researched, some of which are available in the market.
There are evidences that the reduction of the gastrintestinal side effects caused by COX-2 selective inhibitors leads to an adaptative response to the gastric damage, which does not occur when using COX-1 inhibitors (see PESKAR, B. M.; EHRLICH, K.; PESKAR, B. A. “Interaction of cyclooxigenase-2 inhibitor and salicylate in gastric mucosal damage”, European Journal of Pharmacology, v. 434, n. 1-2, p. 65-70, 2002; YAMAMOTO, H. et al. “Inducible types of cyclooxigenase and nitric oxide synthase in adaptive cytoprotection in rat stomachs”, Journal of Physiology, v. 93, p. 405-12, 1999).
On the other hand, there are no studies that demonstrate the differences in efficacy among the COX-2 selective inhibitors, even though there is proof of the reduction of the adverse gastrintestinal effects caused by them. The problem with these inhibitors appears when it is taken into consideration the adverse cardiovascular effects reported by Stacy et al. (see STACY, Z. A.; DOBESH, P. P.; TRUJILLO, T. C. “Cardiovascular risks of cyclooxygenase inhibition”, Pharmacotherapy, v. 26, n. 7, p. 919-938, 2006), being, for this reason, preferred the use of non-selective anti inflammatory drugs.
In fact, the safety of known COX-2 inhibitors have been questioned. The most famous event occurred with the “blockbuster” rofecoxib, with commercial name of Vioxx®, produced by Merck laboratories, which was removed from the market in 2004 after clinical researches demonstrated that it caused a higher risk of heart attack and brain stroke. Other three COX-2 inhibitors that are available in the Brazilian market, celecoxib (Celebra®), valdecoxib (Bextra®) and etoricoxib (ARCOXIA®) are under intense clinical studies in order to verify the safety of their use. In addition, in Apr. 5, 2005, FDA (Food and Drug Administration) has suspended the commercialization of Bextra in the United States and also, in May, 2007, it did not approve the commercialization of Arcoxia.
For all these reasons, the NSAI drugs are still the ones largely used as an important medicamental resource, in spite of the possibility of causing serious known side effects (principally gastric ulceration).
It is still worth mention the role of nitric oxide in the inflammatory processes. In fact, nitric oxide (NO) began to received attention by physiologists with the discovery, in 1986, of Ignaro and collaborators that have described its function as a endothelium derived relaxation factor (EDRF) and have proposed the participation of nitric oxide in the processes of pro inflammatory actions with effects in the vasodilatation and of stimulus of prostaglandins production, as well as anti inflammatory action in order inhibit neutrophyls and platelets, being, therefore, dependent of an immuno-regulated factor (see MONCADA, PALMER, & HIGGS, “The discovery of nitric oxide as the endogenous nitrovasodilator”, Hypertension, v. 12, p. 365-372, 1988).
The nitric oxide is a colorless gas, paramagnetic, water soluble in the proportion of 2-3 moles per dm3 and presents a boiling point around −141.7° C. It is produced in vivo through interaction, catalyzed by enzymes (nitric oxide synthase—NOS), with molecular oxygen and L-arginine (as substrate). Nitric oxide becomes a free radical that, differently from many other free radicals, does not dimerize in the gaseous phase at room temperature and pressure, even though in the liquid state it may form N2O2. When the loss of an electron of the nitric oxide free radical occurs leads to the formation of the nitrosil ion (NO+).
Among the evident chemical properties of nitric oxide, it can be highlighted the possibility of radical formation and, consequently, its biological participation as electrophile, oxidant agent, salt and complex formation agent. In the biological system, the radical form of nitric oxide is associated to other species of nitrogen compounds, such as nitrite (NO2), nitrate (NO3) and peroxynitrite (NO4).
The constitutive isoforms of nitric oxide (cNOS) are subdivided in neuronal (nNOS) and endothelial (eNOS) and, depending in which tissue they are found, they are calcium dependent and can be activated by the calcium binding protein (calmodulin-CaM), through agonists such as acetylcholine (ACh), adenine diphosphate (ADP), bradicinine (Bk) and glutamate (see BARRETO, R. L.; CORREIA, C. R. D.; MUSCARÁ, M. N., “Óxido Nitrico: propriedades e potenciais usos terapëuticos”, Quimica Nova, v. 28, n. 6, p. 1046-1054, 2005).
In addition, nitric oxide acts as a transmitter of the peripherical nervous system and of the urogenital and gastrintestinal tracts.
The induced isoform of nitric oxide (iNOS) is calcium independent and is produced, in high concentrations, by means of activation with bacterial toxins, interpheron and interleukins.
In the defense system, NO is produced by mast cells, macrophages, Kupffer cells and neutrophyls, causing oxidative lesions in the target cell by means of attacking the proteins that are complexed to the membrane.
It is also known the technique to reduce the intestinal mucous membrane damage caused by the anti inflammatory active principles and, at the same time, guaranties a satisfactory absorption of such active principles, through the addition of arginine and similar aminoacids to the pharmaceutical compositions that present protective activity against intestinal mucous membrane damage (see Y. Kinouchi, N. Yata, Biol. Pharm. Bull., 19(3), pp. 375-378 (1996)).
In fact, it is known that L-arginine (NO precursor) protects the gastric mucous membrane from lesion formation, which mechanism probably involves an increase of the blood flux due to the dilatation of adjacent capillars (see KALIA, N. et al. “L-Arginine protects and exacerbates ethanol-induced rat gastric mucosal injury”, Journal Gastroenterology and Hepatology, v. 15, n. 8, p. 915-24, 2000).
Studies performed with the introduction of L-arginine in the treatment with ibuprophen demonstrate a reduction of the oxidative stress and the infiltration of neutrophyls in the gastric mucous membrane, reducing the lesion caused by the anti inflammatory drug. This injury mechanism that depends of the microcirculation is of extreme importance for events of gastrintestinal toxicity caused by NSAI drugs that, in parallel to its therapeutic action, cause damage to the mucous membrane through inflammation mechanism and oxidative lesion monitored by the activity of mieloperoxidases, by the neutrophyllic activation rate, or by lipid peroxidation and activation of xantine oxidase, glutathione peroxidase and superoxide dismutase.
An explanation of the protective activity of L-arginine is the occurrence of a local action that is probably related to the inhibition of the oxidative stress derived from the xantine oxidases, but not to the blockage of the production of free radicals by nuclear polymorph leucocytes (see JIMENEZ, M. D. et al. “Role of L-arginine in ibuprofen-induced oxidative stress and neutrophil infiltration in gastric mucosa”, Free Radical Research, v. 38, n. 9, p. 903-11, 2004).
It is also known that taurine acts in the inflammatory process due to its important activity which is of inhibiting the NO and E2-type prostaglandins production, acting in the suppression of the inducible nitric oxide synthase (iNOS) and in the expression of COX-2 (see LIU, Y. et al. “Taurine Chloramine Inhibits Production of Nitric Oxide and Prostaglandin E2 in Actiated C6 Glioma Cells by Supressing Inducible Nitric Oxide Synthase and Cyclooxigenase-2 expression”, Molecular Brain Research, v. 59, p. 189-195, 1998), as well as in the inhibition of the peroxide ions (see CHAEKYUN, K. et al., “The Production of Superoxide Anion and Oxide by Cultured Murine Leukocytes and the Accumulation of TNF-α in the Conditioned Media is Inhibited by Taurine Chloramine”, Immunopharmacology, v. 34, p. 89-95, 1996).
Another action of taurine is related to the reduction of the hyperanalgesic effects (see THOMAS, G. “Óxido Nitrico” In: Quimica Medicinal: Uma Introdução. Rio de Janeiro: Guanabara Koogan, p. 337-61, 2003), leading to normal levels of NO production, impeding, this way, the active and exacerbated presence of iNOS and inhibiting the arachidonic acid cascade. In fact, in 2001, Palumbo, Cioffi and D'Ischia requested patent for the NOS inhibitory compounds envisioning diverse uses, including inflammatory processes, reinforcing the safety expectation of this therapy (CAN 137:346227; AN 2002:894293; Italian application ITRM20000039 A, published in Jul. 24, 2001), confirming the results of Moncada and Higgs (see MONCADA, S.; HIGGS, E. A. “Molecular mechanisms and therapeutic strategies related to nitric oxide”, FASEB Journal, v. 9, p. 1319-1330, 1995), about the utilization of nitric oxide synthase inhibitors, which represents an advance in the therapy of inflammatory conditions.
The inhibition of the oxidative stress can be explained by the systemic action of aminoacids. In this context, taurine have been presenting advantages related to the systemic action of gastro protection, probably through the suppression of free radicals derived from oxygen, which perform important physiopathologic role in the acute ulceration induced by NSAI drugs and ischemic reperfusion.
The experiment results using taurine as anti oxidant in the intragastric administration in rats pre-treated with 250 mg/kg or 500 mg/kg from 1 (one) to 3 (three) days before hemorrhagic lesion induction by 25 mg/kg of indometacin presented a lesion reduction with the inhibition of lipid peroxidation, besides the inhibition of neutrophyls activity (see SON, M. et al. “Protective effect of taurine on indometacin-induced gastric mucosal injury”, Adv Exp Med Biol, v. 403, p. 147-55, 1996).
It is known, still, that taurine provides a significant reduction of the acid secretion and the increase of the bicarbonate liberation from the lumen due to mechanisms of regulation between the production of nitric oxide and prostaglandins, with a compensatory feedback being kept in the stomach (see TAKEUCHI, K. et al. “Nitric oxide and prostaglandins in regulation of acid secretory response in rat stomach following injury”, Journal of Pharmacology Experimental and Therapeutic, v. 272, n. 1, p. 357-63, 1995).
In addition, it is known that the anti ulcerative activity is closely related to the improvement of the blood flux reduction in the mucous membrane due to the nitric oxide synthesis disturbance, in which the influence of anti ulcerogenic drugs is largely studied, as in the case of the [2,4-diamino-6-(2,5-dichlorophenyl)-S-thiazin]maleate. According to Takashi et al. (TAKASHI, K. et al. “Irsogladine prevents monochloramine-induced gastric mucosal lesions by improving the decrease in mucosal blood flow due to the disturbance of nitric oxide synthesis in rats”, Journal of Pharmacological Sciences, v. 93, p. 314-20, 2003) the action proposal can be demonstrated through the use of constitutive nitric oxide synthase (cNOS) inhibitors or non selective inhibitors such as NG-nitro-L-arginine methyl esther (L-NAME) and inducible nitric oxide synthase (iNOS) selective inhibitors, for example, the aminoguanidin, where the [2,4-diamino-6-(2,5-dichlorophenyl)-S-thiazin]maleate blocks the inhibitory action of cNOS without affecting the action of iNOS which is responsible for cellular recruiting.
As mentioned previously, the nitric oxide perform an important role in the protection of gastric ulceration induced by non steroidal anti inflammatory drugs by means of mechanisms that go beyond acid secretion, leading to a novel route for the treatment of gastric ulceration caused by anti inflammatory drugs. In pre clinic tests using the indometacin as control group of ulceration, it was verified that an 80% increase in gastric acidity with a 22% reduction of nitric oxide (measured as nitrite) occurs. On the other hand, the use of L-NAME does not affect gastric acidity, but causes a 50% reduction in the normal concentrations of nitric oxide and, consequently, the lesion rate doubles (see KHATTAB, M. M.; GAD, M. Z.; ABDALLAH, D. “Protective role of nitric oxide in indometacin-induced gastric ulceration by a mechanism independent of gastric acid secretion”, Pharmacological Research, v. 43, n. 5, p. 463-67, 2001).
The peripherical vascular tonus homeostasis is of great importance in order to maintain the integrity of functional adjacent tissues where the manipulation of the process of NO up-down regulation can lead to thrombosis and ischemic complications, in case of low NO production.
It is important to highlight that, in analyzing the parameters of NO measurements in separate, its subfamilies and production moments must be related to enzymatic activity. This can be an answer to the fact that the use of a simple precursor, such as L-arginine it is not capable of preventing lesion formation in the gastric mucous membrane.
Therefore, the enzymatic substrate (L-arginine) can even increase the presence of NO in exacerbated form in pro inflammatory cells, which, in some way, makes this measure inefficient for blocking free radicals induced in the gastrintestinal inflammatory process.
In this context, taurine plays the role of mediator of a micro circulatory feed-back, besides acting in the inhibition of the enzymatic isoform induced in the inflammatory process. This isoform is responsible for the oxidative stress, then confirming the activity of taurine as gastrintestinal anti oxidant and anti inflammatory drug.
In the investigation of the gastro protector compounds, it was observed that taurine increases cellular resistance in 21%, with maintenance of membrane, mitochondria and nuclear damages integrity (see NAGY, L. et al. “Investigation of gastroprotective compounds at subcellular level in isolated gastric mucosal cells”, American Journal Physiology and Gastrointestinal Liver Physiology, v. 279, n. G1, 201-08, 2000) which reinforces, through elucidation of gastric mucous membrane at subcellular level, the use of taurine as gastro protector compound.
Another proposal of mechanism of action for cytoprotection is based on the adaptation of the endogenous response mediated by prostaglandins without involving the protection pathway effect mediated by nitric oxide. This hypothesis was presented for the activity of L-arginine (NO precursor) against gastric injury, caused in rats, induced by the oral administration of hydrochloric acid (see TAKEUCHI, K. et al. “Cytoprotective action of L-arginine against HCL-induced gastric injury in rats: Involvement of nitric oxide?”, Japan Journal Pharmacology, v. 61, p. 13-21, 1993). The advantage of taurine over L-arginine becomes more evident from the analysis of the results of its use in the reduction of damages to the gastric mucous membrane, because it does not present NO precursor activity.
Although the participation of prostaglandins and nitric oxide in the inhibition of lesion formation induced by necrotic agents is known, there is no clear correlation with the importance degree of these mediators. Nitric oxide inhibition experiments (L-NAME) with supplement of E2 16,16-dimethyl prostaglandin do not cause damage. On the other hand, prostaglandin inhibition with supplement of nitric oxide donor is not sufficient for maintenance of gastric mucous membrane integrity (see UCHIDA, M. et al. “Nitric oxide donating compounds inhibit HCl-induced gastric mucosal lesions mainly via prostaglandin”, Japan Journal Pharmacology, v. 85, p. 133-38, 2001). This study confirms the most evident adverse effect in the therapeutic use of anti inflammatory drugs, as well as the difficulty in lesion reversion or gastroprotection.
Taurine acts in the inflammatory process due to its important activity in inhibiting NO and E2-type prostaglandins (PGE2) production and in acting in the suppression of inducible nitric oxide synthase (iNOS) and in the expression of type-2 cyclooxygenase (see LIU, Y. et al. “Taurine chloramine inhibits production of nitric oxide and prostaglandin E2 in activated C6 glioma cells by suppressing inducible nitric oxide synthase and cyclooxigenase-2 expression”, Molecular Brain Research, v. 59, p. 189-195, 1998), as well as in the inhibition of peroxide ions production (see CHAEKYUN, K. et al. “The production of superoxide anion and oxide by cultured murine leukocytes and the accumulation of TNF-α in the conditioned media is inhibited by taurine chloramine”, Immunopharmacology, v. 34, p. 89-95, 1996).
Many attempts to interfere in the process of gastric lesion formation caused by the NSAI drugs have been made. In the U.S. Pat. No. 7,008,920 it is described the pharmaceutical association between NSAI drugs, bile acid salts and taurine or polyamines in order to reduce the gastrintestinal damage induces by drugs and the increase of their water-solubility.
It is also known that taurine, besides acting against gastric damage (see SENER, G. et al. “Protective effect of taurine against alendronate-induced gastric damage in rats”, Fundamental & Clinical Pharmacology, v. 19, p. 93-100, 2004), it also attenuates kidney hypertension (see HAGAR, H. H.; ETTER, E. E.; ARAFA, M. “Taurine attenuates hypertension and renal dysfunction induced by cyclosporine A in rats”, Clinical and Experimental Pharmacology and Physiology, v. 33, p. 189-196, 2006).
Another important aspect in the search for compounds that attenuate the adverse effects of NSAI drugs and potentate the beneficial effects of these drugs is the development of viable processes of obtaintion under technical and economical point of view. Therefore, numerous researches are being developed in order to obtain novel compounds using, mainly, the molecular modification techniques. Among the obtaintion processes, it is of great importance the latentiation that has the purpose of developing the prodrugs that consist in inactive vehicle forms and that release the drug in vivo after biotransformation (see WERMUTH, C. G. “The Practice of Medicinal Chemistry”, London: Academic Press, 2a ed, 2003. 768 pages; KROGSGAARD-LARSEN, P., BUNDGAARD, H. “A textbook of drug design and the development”, Harwood: Academic Publish, 1991, 643 pages; SILVA, A. T. A. et al. “Advances in prodrug design”, Medicinal Chemistry. v. 5, n. 10, p. 893-914, 2005).
The most current therapeutic chemical compounds have been produced through the latentiation of the original drug, particularly through estherification and amides formation. In a simpler way, it can be said that latentiation is an organic synthesis process that seeks to modify the molecule of an active compound or original drug in order to optimize its pharmacokinetic properties and/or reduce its toxicity.
In the past few years, latentiation has become one of the main tools for the development of chemiotherapic drugs used in the treatment of the major current diseases such as cancer and Acquired Immunodeficiency Syndrome—AIDS. The search for latent drugs is justified by at least one of the following reasons: (i) minimize the pharmacokinetic inconveniences belonging to the original drug, (ii) reduce the high toxicity of the original drug, (iii) perfect the weak chemical stability of the original drug, (iv) improve the water-solubility of the original drug, (v) reduce the inconveniences of odor and taste of the original drug and (vi) make it possible the obtaintion of difficult pharmaceutical formulations due to the original drug.
The latent drugs, called prodrugs, correspond to original drugs that are chemically transformed to an inactive derived compound through chemical reactions, enzymatic reactions or both. The prodrug is converted into the original drug inside the organism prior or after reaching its action spot.
The prodrug can be defined as any compound that undergoes biotransformation before exhibiting its pharmacologic effects. The prodrug as well as the analog of a drug present similar chemical structures, however the biological properties of these compounds differ from the original drug regarding: (i) the activity, (ii) the potency, (iii) the bioavailability, (iv) the synthesis process, (v) the action spectrum, and (vi) therapeutic index. The prodrug differs from the analog drug due to the in vivo hydrolysable chemical bond and the transporter group.
Among the various prodrugs obtaintion methods, estherification is the most employed one, followed by amide, imide and carbamate formation. Currently, drug functional groups can be modified through chemical reactions producing reversible groups heavily used in the development of prodrugs.
Countless substitutions in known molecules as well as novel NSAI-derived drugs are described in the state of the technique seeking to improve not only their adverse effects as well as their anti inflammatory potential. For example, the U.S. Pat. No. 5,905,073 patent described 5-ASA and other NSAI-derived prodrugs for treating ulcerative colitis.
Among the commercially available NSAI drugs, diclophenac is one of the most used anti inflammatory drugs. In fact, diclophenac, discovered in 1966 and described in the U.S. Pat. No. 3,558,690, is one of the best seller drugs in the world and its efficacy and safety is established in the anti inflammatory therapy field. Various substitutions have also been made in 2-arylaminophenylacetic acids in order to reduce the deleterious side effects of this active principle, being described in several patent documents, such as, for example U.S. Pat. Nos. 3,652,762; 4,173,577; 4,166,128; 4,704,468; 5,475,139; WO 9404484; WO 9709977; WO 9600716 and DE 345011.
The aceclophenac is an example of diclophenac prodrug, described in the U.S. Pat. No. 4,548,952, obtained through the estherification of the carboxylic group by an small alkyl chain, in an attempt of reducing the deleterious effects in the gastrintestinal tract when used in anti inflammatory therapies. For example, the U.S. Pat. No. 6,451,858 described estherifications in 2-arylaminophenylacetic acids as an attempt of increasing its selectivity towards COX-2.
Other modifications in the diclophenac molecule were performed in order to reduce undesired side effects or to increase its bioavailability to make other administration options besides oral viable, being cited: (i) the U.S. Pat. No. 4,704,468 that describes double diclophenac prodrugs linked by polyethylene glycol-derived compounds in order to reduce the gastric effects and (ii) the U.S. Pat. No. 5,792,786 that describes NSAI drugs estherifications with long chained fatty acids in order to increase their bioavailability in topic use pharmaceutical forms.
Still in order to reduce the prejudicial effects caused by NSAI drugs in patients presenting inflammatory disturbances, more recently, researches has been directed to the a more detailed study of the functions performed by nitric oxide in the biological systems. In this context, the U.S. Pat. No. 5,597,847 describes 2-arylaminophenylacetic acids-derived compounds that were nitrated in order to increase their anti inflammatory potential seeking to provide nitric oxide in the inflammatory process. In a similar way, prodrugs with NO local release are described in the patent document WO 2006125016.
The WO 9109831 document describes NSAI-derived prodrugs with acid groups obtained through anhydride formation among groups present in the NSAI drug itself or in different NSAI drugs, such as ASA, SA (salicylic acid), sulindac, cetoprophen, indometacin, naproxen, fenoprophen, ibuprophen, diflunisal, tolmetin, flurbiprophen, suprophen.
Other prodrug obtaintion examples are presented in the U.S. Pat. No. 5,681,964 that describes indometacin estherifications, resulting in reduction of gastric damages; in the U.S. Pat. Nos. 5,607,966 and 5,811,438 that describe esther derived compounds and indometacin amides used as antioxidants and 5-lipoxygenase inhibitors, without, however, presenting COX-2 selectivity; in the U.S. Pat. No. 6,399,647 that describes indometacin-derived sulphonamidic compounds presenting an increase in COX-2 selectivity; and in the U.S. Pat. No. 6,887,903 that describes sulphonamidic derived compounds that act in other pathways of the inflammatory process as signaling molecules of nuclear polymorph neutrophyls and other interleukins.
In spite of this diversity of NSAI prodrugs have presented advantages regarding the original drugs, there are still various deleterious effects that limit their use.
Taurine and other specific aminoacids present themselves as interesting drug transporters, enabling an improvement not only in physico-chemical, but also reducing its adverse effects. The U.S. Pat. No. 5,059,699 presents taxol-derived compounds (antineoplasic) and taurine to increase its water-solubility, leading to the increase of its bioavailability and stability in chemiotherapeutical formulas. Other formula improvement examples using taurine are based on salicylate-derived compounds (SA and ASA) or in sulphonamidic-derived compounds as described in the documents JP68003293 and JP68004331.
The limitations and disadvantages of known prodrugs and drugs led to the search for novel active principles disclosed herein, which minimizes the deleterious effects of the NSAI drugs. Hence, the present invention results from the knowledge of mechanisms of action of the anti inflammatory drugs described by the therapeutic field, exploring their potential in the use of NSAI-derived drugs during chronic anti inflammatory treatments.
Therefore, the objective of the present invention is to is the pharmacotherapeutic that involves acute and chronic treatments with anti inflammatory drugs seeking reduce or annul the adverse effects of gastric ulceration from the discovery that aminoacids associated to anti inflammatory administered orally reduce the extension of the gastric lesion, where taurine present an important role in this mechanism, particularly regarding to its participation in the pro inflammatory cytokines regulation process.